Implication of metabolism in the polarization of tumor-associated-macrophages: the mass spectrometry-based point of view

Tumor-associated macrophages (TAMs) represent one of the main tumor-infiltrating immune cell types and are generally categorized into either of two functionally contrasting subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. TAMs showed different activation states that can be represent by the two extremes of the complex profile of macrophages biology, the M1-like phenotype (pro-inflammatory activity) and the M2-like phenotype (anti-inflammatory activity). Based on the tumor type, and grades, TAMs can acquire different functions and properties; usually, the M1-like phenotype is typical of early tumor stages and is associated to an anti-tumor activity, while M2-like phenotype has a pro-inflammatory activity and is related to a poor patients’ prognosis. The classification of macrophages into M1/M2 groups based on well-defined stimuli does not model the infinitely more complex tissue milieu where macrophages (potentially of different origin) would be exposed to multiple signals in different sequential order. This review aims to summarize the recent mass spectrometry-based (MS-based) metabolomics findings about the modifications of metabolism in TAMs polarization in different tumors. The published data shows that MS-based metabolomics is a promising tool to help better understanding TAMs metabolic phenotypes, although it is still poorly applied for TAMs metabolism. The knowledge of key metabolic alterations in TAMs is an essential step for discovering TAMs polarization novel biomarkers and developing novel therapeutic approaches targeting TAM metabolism to repolarize TAMs towards their anti-tumor phenotype

Use of contrast-enhanced intraoperative ultrasonography during liver surgery for colorectal cancer liver metastases - Its impact on operative outcome. Analysis of a prospective cohort study

Abstract Background Preliminary reports led to discordant conclusions concerning the use of contrast-enhanced intraoperative ultrasonography (CE-IOUS) during surgery for colorectal liver metastases (CLM). The aim of this study was to evaluate the impact of CE-IOUS in patients undergoing surgery for CLM using an advanced preoperative imaging work-up, and well-established reference standards. Materials and methods Forty-seven consecutive patients underwent liver resection using IOUS and CE-IOUS for CLM. All patients underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI) within 2 weeks prior to surgery. CE-IOUS was performed by injecting intravenously 4.8 ml of sulphur-hexafluoride microbubbles (SonoVue, Bracco, Italy). Reference standards were histology, and 6-month imaging follow-up. Results IOUS discovered 43 additional lesions in 20 patients. CE-IOUS found 10 additional lesions not seen at IOUS in four patients, and confirmed all the IOUS findings. Fourteen CLM in 10 patients appeared within 6 months after surgery. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were, respectively: 66%, 0%, 98%, 0% and 65% for CT + MRI; 88%, 100%, 100%, 8%, 88% for IOUS and 93%, 100%, 100%, 13%, 93% for IOUS + CE-IOUS. In nine patients CE-IOUS afforded better definition of tumour margins thus helping in resection guidance. Conclusions CE-IOUS improves IOUS findings both for detection and for resection guidance. The combination of IOUS and CE-IOUS should be considered routinely in patients operated for CLM

Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma.

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Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma

: Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance

Inhibitors of apoptosis proteins (IAPs) expression and their prognostic significance in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>Similarly to other tumor types, an imbalance between unrestrained cell proliferation and impaired apoptosis appears to be a major unfavorable feature of hepatocellular carcinoma (HCC). The members of IAP family are key regulators of apoptosis, cytokinesis and signal transduction. IAP survival action is antagonized by specific binding of Smac/DIABLO and XAF1. This study aimed to investigate the gene and protein expression pattern of IAP family members and their antagonists in a series of human HCCs and to assess their clinical significance.</p> <p>Methods</p> <p>Relative quantification of IAPs and their antagonist genes was assessed by quantitative Real Time RT-PCR (qPCR) in 80 patients who underwent surgical resection for HCC. The expression ratios of XIAP/XAF1 and of XIAP/Smac were also evaluated. Survivin, XIAP and XAF1 protein expression were investigated by immunohistochemistry. Correlations between mRNA levels, protein expression and clinicopathological features were assessed. Follow-up data were available for 69 HCC patients. The overall survival analysis was estimated according to the Kaplan-Meier method.</p> <p>Results</p> <p>Survivin and Livin/ML-IAP mRNAs were significantly over-expressed in cancer tissues compared to non-neoplastic counterparts. Although Survivin immunoreactivity did not correlate with qPCR data, a significant relation was found between higher Survivin mRNA level and tumor stage, tumor grade and vascular invasion.</p> <p>The mRNA ratio XIAP/XAF1 was significantly higher in HCCs than in cirrhotic tissues. Moreover, high XIAP/XAF1 ratio was an indicator of poor prognosis when overall survival was estimated and elevated XIAP immunoreactivity was significantly associated with shorter survival.</p> <p>Conclusion</p> <p>Our study demonstrates that alterations in the expression of IAP family members, including Survivin and Livin/ML-IAP, are frequent in HCCs. Of interest, we could determine that an imbalance in XIAP/XAF1 mRNA expression levels correlated to overall patient survival, and that high XIAP immunoreactivity was a poor prognostic factor.</p

ERS: A simple scoring system to predict early recurrence after surgical resection for hepatocellular carcinoma.

peer reviewed[en] BACKGROUND: Surgical resection (SR) is a potentially curative treatment of hepatocellular carcinoma (HCC) hampered by high rates of recurrence. New drugs are tested in the adjuvant setting, but standardised risk stratification tools of HCC recurrence are lacking. OBJECTIVES: To develop and validate a simple scoring system to predict 2-year recurrence after SR for HCC. METHODS: 2359 treatment-naïve patients who underwent SR for HCC in 17 centres in Europe and Asia between 2004 and 2017 were divided into a development (DS; n = 1558) and validation set (VS; n = 801) by random sampling of participating centres. The Early Recurrence Score (ERS) was generated using variables associated with 2-year recurrence in the DS and validated in the VS. RESULTS: Variables associated with 2-year recurrence in the DS were (with associated points) alpha-fetoprotein (100: 3), size of largest nodule (≥40 mm: 1), multifocality (yes: 2), satellite nodules (yes: 2), vascular invasion (yes: 1) and surgical margin (positive R1: 2). The sum of points provided a score ranging from 0 to 11, allowing stratification into four levels of 2-year recurrence risk (Wolbers' C-indices 66.8% DS and 68.4% VS), with excellent calibration according to risk categories. Wolber's and Harrell's C-indices apparent values were systematically higher for ERS when compared to Early Recurrence After Surgery for Liver tumour post-operative model to predict time to early recurrence or recurrence-free survival. CONCLUSIONS: ERS is a user-friendly staging system identifying four levels of early recurrence risk after SR and a robust tool to design personalised surveillance strategies and adjuvant therapy trials

Reply to "Application of contrast-enhanced intraoperative ultrasonography in the decision-making about hepatocellular carcinoma operation"

The use of contrast-enhanced intraoperative ultrasound for hepatocellular carcinoma has been already proposed as a novel technique to stage the disease during surgical resection. In the herein presented “letter to the editor”, the authors underline some important points, which have been raised following paper published in the January issue of World Journal of Gastroenterology